The proposed studies will explore Mycobacterium leprae foot pad infection in knockout (KO) mouse strains carefully selected for their disruption in genes that play key roles in host cell mediated immunity (CMI) to mycobacterial pathogens. Growth of M. leprae in the foot pad will be monitored and the experimental granulomas which develop will be analyzed to determine if these KO mouse strains can serve as models for the key immunoregulatory elements of CMI that result in the unique immunopathological spectrum of human leprosy. CMI responses will be further modified in the KO mice by conditionally knocking-out additional gene products before or after infection with M. leprae or by selectively restoring certain disrupted gene functions after infection. Development of KO mouse models for discrete elements of the human leprosy spectrum should open investigation into the mechanisms underlying the instability inherent to the borderline area of this spectrum where downgrading and upgrading shifts toward the lepromatous and tuberculoid ends of the spectrum, respectively, are poorly understood. More importantly, KO mouse models of leprosy and the additional manipulations of these models that are proposed may afford insight into the mechanisms responsible for the abrupt onset of type 1 and type 2 reactions. Ultimately, this basic knowledge may permit prediction and prevention of these devastating reactions, which markedly enhance nerve damage. Numerous studies have been reported with M. tuberculosis in gene KO mice. We suggest that M. leprae-KO mouse studies will permit more detailed dissection of the mechanisms of CMI. Targeted removal of a number of isolated gene functions often greatly exacerbates experimental murine tuberculosis, perhaps by overwhelming certain compensatory mechanisms in host resistance. In marked contrast, M. leprae is a quiet, well adapted, obligate intracellular pathogen. This proposal is based on the likelihood that its characteristics of slow rate of growth, low virulence and chronic pathogenesis are the very attributes which will make the study of M. leprae in targeted gene KO mice an ideal model for analyzing the principal redundant and compensatory mechanisms of CMI in host resistance to infection in general and to intracellular mycobacterial pathogens in particular.